Macrophages secrete cytokines and chemokines that are important for coordinating immune responses. Release of the chemokine CCL2 by macrophages and macrophage migration into bacterially infected tissues in mice requires the expression of transient receptor potential cation channel, mucolipin subfamily member 2 (TRPML2). To better understand how TRMPL2 regulates macrophage function, Plesch et al. developed compounds that selectively activated TRMPL2 but not the related channels TRPML1 or TRPML3 (see commentary by Galione and Davis). The specificities of the identified compounds were verified by patch clamp measurements of ion flux on endosomes isolated from cells that expressed one of the three TRPML family members. The TRPML2-selective agonist promoted ion flux on endolysosomes from bone marrow–derived and lung alveolar macrophages only after the cells were treated with the bacterial compound lipopolysaccharide (LPS), which increased TRPML2 abundance. Additionally, the authors found that acidic vesicular pH decreased TRPML2 activity, whereas it increased the activity of TRPML1. Molecular modeling of the agonist in complex with TRPML1 or TRPML2 identified potential contact residues, and a G425A mutation abrogated the effects of the TRPML2-selective agonist. Activating TRPML2-mediated ion flux with the agonist increased the amount of CCL2 secreted by the macrophages and enhanced transferrin receptor removal from the plasma membrane, which is suggestive of increased endosomal recycling. In contrast, the TRPML2 agonist had no effect on common markers of lysosomal export, hexosaminidase release and cell-surface LAMP1 abundance. These data suggest that TRPML2-mediated ion flux on early or recycling endosomes may be important for CCL2 export by macrophages through this cellular compartment.